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Use of opioids for chronic non-cancer pain is controversial and the efficacy of comprehensive pain rehabilitation programs (CPRPs) that incorporate opioid withdrawal requires further investigation. We test the hypothesis that patients with chronic pain and longstanding opioid use who undergo opioid withdrawal in the course of rehabilitative treatment will experience significant and sustained improvement in pain and functioning similar to patients who were not taking opioids. A longitudinal design study compared 373 consecutive patients admitted to the Mayo Clinic Pain Rehabilitation Center at admission, discharge and six-month posttreatment by opioid status at admission. Measures of pain severity, depression, psychosocial functioning, health status, and pain catastrophizing were used to assess between- and within-group differences. Treatment involved a 3-week interdisciplinary pain rehabilitation program focused on functional restoration. Over one-half of patients (57.1%) were taking opioids daily at admission. The majority of patients (91%) completed rehabilitation and 70% of patients who completed the program returned questionnaires six months posttreatment. On admission, patients taking low- and high-dose opioids reported significantly greater pain severity (P = .001) and depression (P=.001) than the non-opioid group. Significant improvement was found on all outcome variables following treatment (P < .001) and six-month posttreatment (P < .001) regardless of opioid status at admission. There were no differences between the opioid and non-opioid groups upon discharge from the program or at six months following treatment. Conclusion: Patients with longstanding CPRP on chronic opioid therapy, who choose to participate in interdisciplinary rehabilitation that incorporates opioid withdrawal, can experience significant and sustained improvement in pain severity and functioning.